Nucleosides. 139. Synthesis and anticytomegalovirus and antiherpes simplex virus activity of 5’-modified analogues of 2’-fluoroarabinosylpyrimidine nucleosides Journal Article
| Authors: | Harada, K.; Matulic-adamic, J.; Price, R. W.; Schinazi, R. F.; Watanabe, K. A.; Fox, J. J. |
| Article Title: | Nucleosides. 139. Synthesis and anticytomegalovirus and antiherpes simplex virus activity of 5’-modified analogues of 2’-fluoroarabinosylpyrimidine nucleosides |
| Abstract: | In order to determine if modification of the 5’-position reduces or abolishes the antiviral activity of 2/-fluoro-5-iodo-ara-C (FIAC), 2’-fluoro-5-iodo-ara-U (FIAU), or 2/-fluoro-5-methyl-ara-U (FMAU) against human cytomegalovirus (HCMV) and herpes simplex virus (HSV), the 5’-deoxy, 5’-mercapto, and 5’-amino analogues of these nucleosides were prepared. 5’-Deoxy-FIAC and 5’-deoxy-FIAU were prepared by catalytic hydrogenation of 5’-iodo-FIAC and 5’-iodo-FIAU to 5’-deoxy-FAC and 5’-deoxy-FAU respectively, followed by reiodination at C-5. Reduction of 5’-iodo-FIVfAU afforded 5’-deoxy-FMAU. These 5’-deoxy nucleosides were found to be inactive against HCMV, indicating that the conversion to 5’-phosphate by the cellular enzyme(s) is a requirement for antiviral activity against this virus. Other 5’-modified (NH2and SH) analogues were also prepared from 5’-O-tosyl-FIAC and 5’-O-tosyl-FMAU. Treatment of these tosylates with LiN3in DMF afforded the corresponding 5'-N3products. Catalytic hydrogenation of 5'-N3-FMAU afforded 5/-NH2-FMAU, whereas 5'-NH2-FIAC was obtained by treatment of 5'-N3-FIAC with Ph3P in pyridine. 5r-Mercapto analogues were prepared by treatment of 5' -O-tosy1-3’-O-acetyl nucleosides with KSAc followed by deacetylation. 5/-NH2-FMAU was the only compound that showed good activity against HSV-1 and HSV-2 in vitro. However, this compound was less potent and had a lower therapeutic index than FMAU. © 1987, American Chemical Society. All rights reserved. |
| Keywords: | unclassified drug; drug efficacy; nonhuman; cytarabine; animals; in vitro study; drug screening; drug evaluation, preclinical; drug synthesis; structure activity relation; structure-activity relationship; simplexvirus; arabinofuranosyluracil; magnetic resonance spectroscopy; fialuridine; antivirus agent; drug cytotoxicity; herpes simplex virus; nuclear magnetic resonance; cytomegalovirus; uridine; vero cells; antiviral agents; indicators and reagents; drug identification; fluorine; intoxication; drug comparison; clevudine; fiacitabine; nucleoside derivative; priority journal; article; drug analysis; 2',5' dideoxy 2' fluoro 5 iodo 5 mercaptouracil arabinoside; 2',5' dideoxy 2' fluoro 5 iodocytarabine; 2',5' dideoxy 2' fluoro 5 iodouracil arabinoside; 2',5' dideoxy 2' fluorothymidine arabinoside; 5' amino 2',5' dideoxy 2' fluoro 5 iodouracil arabinoside; 5' amino 2',5' dideoxy 2' fluorothymidine arabinoside; pyrimidine 2' deoxy 2' fluoroarabinofuranoside derivative |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 30 |
| Issue: | 1 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 1987-01-01 |
| Start Page: | 226 |
| End Page: | 229 |
| Language: | English |
| DOI: | 10.1021/jm00384a041 |
| PUBMED: | 3027334 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 5 February 2021 -- Source: Scopus |
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